PROJECT SUMMARY/ABSTRACT Identification of small molecules that extend mouse lifespan provides new insights into mechanisms of longevity determination in mammals, and may lay the groundwork for eventual anti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agents proposed to extend mouse lifespan by retarding aging or postponing late life diseases. Interventions proposed by multiple collaborating scientists from the research community are tested, in parallel, at three sites (The Jackson Laboratory, University of Michigan and University of Texas), using identical, standardized protocols. Sufficient numbers of genetically heterogeneous mice are used to provide 80% power for detecting a 10% change in lifespan of either sex, after pooling data from any two of the test sites. Seventy-two such lifespan experiments, involving various doses of 44 distinct agents, have been initiated in the first fifteen years of the ITP. Thirty-seven experiments have involved comparative tests of multiple doses of effective agents, variable starting ages, or alternative dosing schedules. Significant effects on longevity, in one or both sexes, have been documented and then confirmed for NDGA, rapamycin, acarbose, and 17-?-estradiol (17aE2), with significant (but currently unconfirmed) effects also noted for Protandim, glycine and, in an interim analysis, canagliflozin. Lifespan trials are now underway for 18 new agents. ITP survival results have also documented longevity benefits from three agents started in middle- age: rapamycin, acarbose, and 17aE2. The previous five-year period has introduced three new features to the ITP: 1) increased emphasis on health outcomes (functional tests relevant to human health not necessarily linked to lifespan); 2) a Collaborative Interactions Program to provide tissues from ITP drug-treated mice to a growing, international network of scientific collaborators; and, 3) a publicly accessible data repository and display engine hosted by the Mouse Phenome Database at The Jackson Laboratory. Plans for the next five- year period include additional lifespan (Stage I) trials, detailed analyses (Stage II) of agents found to increase lifespan, continued growth in data on health outcomes, and collaborative work with scientists to study drug effects on postulated aging mechanisms and links to disease. Studies at The Jackson Laboratory will follow a wide variety of health outcomes measured with minimal stress, add more cognitive function tests, add longitudinal analyses, and study successful interventions in mouse models of aging diseases such as diabetes and dementia. The work proposed should allow the ITP to continue to make major contributions to mammalian aging biology.